Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching

doi:10.1016/S0960-894X(03)00626-7

Bioorganic & Medicinal Chemistry Letters

Volume 13, Issue 18, 15 September 2003, Pages 2967-2971

https://doi.org/10.1016/S0960-894X(03)00626-7 Get rights and content

Abstract

The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.

Abstract

The discovery of a new class of inhibitors of the kinase activity of the vascular endothelial growth factor tyrosine kinase receptors KDR and Flt-1 is described.

Introduction

Inhibition of tumor induced angiogenesis is a promising strategy in anticancer drug research.1, 2 Selective inhibition of the tyrosine kinase enzymatic activity of the two vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 is an approach3, 4, 5, 6, 7 we are pursuing in this area.

In this respect, we have previously reported the discovery of the anilinophthalazine compound PTK787/ZK222584 (1), a potent and selective inhibitor of the kinase activity of KDR and Flt-1, which is currently undergoing clinical evaluation.8, 9 More recently, we have disclosed anthranilic acid amide derivatives, which represent a novel chemical class of inhibitors of these enzymes, with promising in vivo antitumor effects.¹⁰ In this article, we describe how, following a line of reasoning based on a conformational analysis of 1, this new class of angiogenesis inhibitors was discovered.

Section snippets

Conformational Analysis of Compound 1

As 1 was identified by high-throughput screening and not by structure-based design or pharmacophore modeling, the structural and conformational determinants of its kinase inhibitory activity were completely unknown initially. As part of our efforts to elucidate these, we undertook a conformational analysis of the inhibitor by computational methods.¹¹

This analysis provided a set of 24 energy-minimized conformations that could be classified in two subsets corresponding, respectively, to an anti

Chemistry

The synthesis of compound 1, Scheme 1 is summarized in Scheme 1.²³ Anthranilic acid was converted to its BOC-protected derivative 4,²⁴ which upon HBTU activation was reacted with p-chloro aniline to provide anilide 5.²⁵ Following removal of the BOC-protecting group with 4 N HCl/dioxane, reductive amination of the resulting amine 6²⁶ with pyridine-4-carbaldehyde in the presence of NaCNBH₃ gave the desired compound 1, Scheme 1²⁷ as white crystals in 33% yield.

Conclusion

As the result of an investigation aimed at understanding the conformational and structural basis of the KDR/Flt-1 inhibitory activity of 1, we identified a new class of inhibitors of these enzymes that possess potent antiangiogenic and antitumor properties.¹⁰ In the era of high throughput approaches to drug discovery, where it is believed that the screening or synthesis of very large numbers of compounds are required, the work reported here illustrates that large scale experimental effort is

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Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching

Abstract

Abstract

Introduction

Section snippets

Conformational Analysis of Compound 1

Chemistry

Conclusion

Drug Discov. Today

Drug Discov. Today

Curr. Opin. Chem. Biol.

Pharmacol. Ther.

Bioorg. Med. Chem. Lett.

Structure

J. Mol. Graph

Carcinogenesis

Cancer Res.

Curr. Top. Med. Chem.

J. Med. Chem.

Drugs Future

J. Med. Chem.

Curr. Med. Chem.